tbuckley/cabot-search huggingface dataset:
Sustained organ preservation in patients with rectal cancer treated with total neoadjuvant therapy: Long-term results of the OPRA trial.
Authors: Floris S Verheij, Dana Mohamed Rashid Omer, Hannah Williams, James T Buckley, Sabrina T Lin, Li-Xuan Qin, Hannah M Thompson, Jonathan B Yuval, Marc J Gollub, Abraham Jing-Ching Wu, Leonard B. Saltz, Julio Garcia-Aguilar
Journal: Journal of Clinical Oncology (2023)

3520 Background: The preliminary results of the OPRA trial demonstrated that a substantial number of patients with locally advanced rectal cancer treated with total neoadjuvant therapy (TNT) could achieve organ preservation. Although most tumor regrowths seem to occur within the first 3 years, longer follow-up is needed to assess the ongoing risk of regrowth. Here, we report the long-term organ preservation rate and oncologic outcomes of the OPRA trial. Methods: A prospective, multi-institutional phase II trial, in which patients with stage II or III rectal cancer were randomized to receive either induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients underwent reassessment for treatment response 8-12 weeks after TNT. Patients who achieved a complete or near-complete response after finishing TNT were offered a watch and wait approach (WW). Those with incomplete response were recommended total mesorectal excision (TME). We report 5-year disease-free survival (DFS), organ preservation (defined as TME-free survival), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS) for each treatment group. We also compared DFS between patients who underwent upfront TME after restaging and patients who underwent TME after tumor regrowth. All analyses followed the intention-to-treat principle and groups were compared using the log-rank test. Results: Of the 324 patients randomized, 158 were assigned to the INCT-CRT group and 166 to the CRT-CNCT group. Median follow-up was 56 months; 85 DFS events were observed. The rates of 3- and 5-year DFS, TME-free survival, LRFS, DMFS and OS are listed in the Table. In total, 80 of the 225 (36%) patients who started WW developed a regrowth; 94% occurred within 2 years and 99% occurred within 3 years. The rate of TME-free survival at 5 years was significantly higher for CRT-CNCT (54%) than in INCT-CRT (39%). 5-year DFS was similar for patients who underwent TME after restaging (61%) compared to patients who underwent TME after regrowth (62%, p = 0.86). Conclusions: In patients with rectal cancer treated with TNT and WW, the majority of tumor regrowths occur in the first 2 years, and regrowth after 3 years is vanishingly rare. Salvage TME for tumor regrowth during WW appears to offer similar outcome to immediate TME after incomplete response to TNT. Distant metastases remain the most frequent cause of treatment failure, with similar rates in the two treatment groups. Clinical trial information: NCT02008656 . [Table: see text]
Qualitative analysis of barriers to precision oncology within the VHA.
Authors: Daniel Jacob Becker, Alexander Michael Barbaro, Kenneth Csehak, Kevin Diasti, Stefanie D. Roman, Danil V. Makarov, Scott Sherman, Allison P. Squires
Journal: Journal of Clinical Oncology (2023)

e18760 Background: Rapidly expanding knowledge of molecular drivers of cancer helps facilitate effective, targeted cancer therapy (i.e. precision oncology), but research suggests that precision oncology is underused. We conducted a qualitative study of barriers and facilitators of precision oncology use within the Veterans Health Administration (VHA). Methods: We conducted a pragmatic qualitative study involving semi-structured interviews with both patients and providers at VA medical centers with low, medium, and high guideline concordant molecular testing. The interview guide was constructed by a multidisciplinary team of oncologists, qualitative health researchers and patient representatives using modified grounded theory (MGT) and the Theoretical Domains Framework (TDF). Summative and directed content analyses were conducted. Codes for the directed content analysis came from the framework and others evolved iteratively. Consensus-based approaches finalized the codebook. Results: Thirty-three interviews were conducted (17 patient and 16 provider interviews). A total of 1889 unique phrases were identified and categorized into 255 meaningful statement codes. The codes were mapped to 10 TDF domains. The most frequently cited determinants, representing 59% (1110 of 1889 statements) of all coded data, included the domains environmental context and resources, knowledge, and goals. Both patients and providers shared similar goals of improved outcomes and quality of care, but systems barriers were frequently cited impediments to precision oncology use. An additional 27% of codes (510 of 1889) represented the TDF domains of emotions (predominantly patient “fear of genetics” and confidence in providers), memory/attention (task priority in clinic visits), and interpersonal skills (both patient-provider, and interdisciplinary provider-provider). Additional frequently cited determinants, each comprising 6% of coded statements, included social influences (for both providers and patients) and reinforcement (perceived consequences). Conclusions: We identified determinants of precision oncology use at the patient, provider, and system level. Attempts to improve implementation of precision oncology will need to address systems barriers to care, as well as knowledge and patient-provider interactions, but can build on a foundation of shared goals.
Optimal molecular-targeted therapies as first-line treatment for <i>RAS</i> wild-type, right-sided metastatic colorectal cancer from the Analysis and Research in Cancers of the Digestive System (ARCAD) database.
Authors: Kentaro Yamazaki, Yuriko Takeda, Toshihiro Misumi, Motoko Suzuki, Masashi Wakabayashi, Hideaki Bando, Eiji Oki, Jean-Yves Douillard, Cornelis J. A. Punt, Eric Van Cutsem, Carsten Bokemeyer, Alan P. Venook, Yoshihiko Maehara, Volker Heinemann, Chiara Cremolini, Goro Nakayama, Thierry Andre, Qian Shi, Aimery De Gramont, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2023)

3588 Background: Although anti-EGFR antibody plus doublet chemotherapy has become the standard of first-line treatment for RAS wild-type (wt), left sided metastatic colorectal cancer (mCRC), the optimal molecular-targeted therapy for RAS wt, right-sided mCRC is not clear. Methods: To evaluate the efficacy between anti-EGFR antibody vs. bevacizumab combination therapy, from 40,889 Individual patient (pt) data from 59 studies in ARCAD mCRC database, 723 pts with RAS wt, right-sided mCRC who received a first-line molecular-targeted therapy with backbone chemotherapy (FOLFOX/FOLFIRI when anti-EGFR antibody combination, and FOLFOX/FOLFIRI/CAPOX/FOLFOXIRI when bevacizumab combination) were selected from 10 randomized studies (FIRE-3, CALGB80495, CRYSTAL, PRIME, CAIRO2, OPUS, TRIBE, TRIBE2, ATOM, and CCOG1201). Primary objective was overall survival (OS), and secondary objectives were progression-free survival (PFS) and overall response rate (ORR); Hazard ratio (HR) and Odds ratio (OR) were adjusted for ECOG-PS, age, and gender. Propensity score matching (PSM) and inverse probability treatment weighting (IPTW) as sensitivity analysis were also performed. Secondary analyses were limited to BRAF wt pts. Results: Anti-EGFR antibody and bevacizumab were administrated in 329 and 394 pts, respectively, of whom 162 and 151 pts were BRAF wt, respectively. Baseline characteristics were as follows (anti-EGFR antibody/bevacizumab): median age, 63.0 years both; female, 47.1/46.4%; and ECOG-PS 0, 53.2/65.2%. The OS and PFS were significantly prolonged in pts receiving bevacizumab combination therapy compared to those receiving anti-EGFR antibody combination therapy (Table). These trends were more pronounced when limited to BRAF wt pts (Table). There were no significant differences in ORR for both overall and BRAF wt pts. These results were similar in the sensitivity analysis (Table). Conclusions: For patients with RAS wt or RAS/ BRAF wt, right-sided mCRC, bevacizumab combination therapy is preferred first-line treatment. [Table: see text]
Comprehensive analysis of molecular characteristics, TMB, and MSI in Chinese patients with neuroendocrine neoplasms.
Authors: Xiaohan Li, Yun Xiao, Juan Ma, Ran Ding, Chenxi Wang, Wanglong Deng, Fanfeng Bu
Journal: Journal of Clinical Oncology (2023)

e16236 Background: Neuroendocrine neoplasms (NENs) is a heterogeneous and rare tumor type. To date, most genomic profiling studies on NENs have mainly focused on pancreatic NENs (PanNENs), less is known about nonpancreatic NENs (NP-NENs). We explored the molecular characteristics, tumor mutational burdens (TMB) and microsatellite instability (MSI) in Chinese NENs patients based on different primary lesions to discover genomic profiles. Methods: We retrospectively analyzed molecular characteristics, TMB and MSI in 155 Chinese NENs patients from laboratory of Simcere Diagnosis (Nanjing, China) during 2019 to 2022. Tissue and plasma samples were profiled using the 551-gene panel next-generation sequencing (NGS). Results: The median age of 155 patients was 61 years old (range, 22-85 years old), the male to female ratio was 1.63:1. 118 cases with known primary lesions could be divided into PanNENs(n=22) and NP-NENs (n=96). There were no differences in age and ratio of PanNENs and NP-NENs. The most common SNV and indel mutations were TP53(23%), DAXX (22.7%), MEN1 (18.2%), KRAS (18.2%), ATM (13.6%), SMAD4 (13.6%) and TSC2 (13.6%) in PanNENs, in which CDK4/6 amplifications were often detected (31.8%, 27.3%). Gene fusions rarely occurred in this cohort. For NP-NENs, we identified TP53 (58.3%), MUC16 (29.2%), RB1(31.3%), LRP1B (22.9%), SMARCA4 (10.4%), SPTA1 (10.4%) and FAT3 (10.4%) as the most common SNV and indel mutations, with MYC (26%) and CDK4 (15.6%) amplifications. CCNE1 high-level amplification was especially common in digestive system NENs. Multiple gene fusions were found in NP-NENs. 13/155 (8.4%) patients carried pathogenic/likely pathogenic germline mutations in MUTYH(n=3), MSH3 (n=2), FANCG (n=2), RAD51D (n=1), CDH1 (n=1), ERCC3 (n=1), ATM (n=1), MEN1 (n=1), RECQL4 (n=1), most of them were associated with DNA damage repair (DDR) pathway. 92.3% (12/13) patients were NP-NENs with only one PanNENs harboring MUTYH germline mutation. 155 NEN patients could be evaluated for TMB, 24 (15.5%) patients had TMB≥10Muts/Mb, 7% (10/24) were lung-derived NENs. TMB was significantly higher in NP-NENs compared to PanNENs (4.26 muts/Mb vs. 2.13muts/Mb, P&lt;0.01). 138 patients could be evaluated for MSI status, only one NEN whose primary site was liver was MSI-H, the others were all MSS. Conclusions: Our data showed that PanNENs and NP-NENs had different mechanisms of tumorigenesis: DAXX and MEN1 alterations commonly identified in PanNENs primarily mediate DDR and PI3K-mTOR pathway. Frequent TP53, RB1 and CCNE1 aberrations in NP-NENs were associated with CDK signaling pathway. TMB was low in almost all NENs exclude lung-derived NENs. It revealed distinct drivers in different subtypes, potentially being used as relevant therapeutic targets.
Influence of high COL19A1 expression on the effectiveness of neoadjuvant immunotherapy plus chemotherapy and long-term survival in patients with esophageal squamous cell carcinoma.
Authors: Jianhua Liu, Jia-Tao Zhang, Changbin Zhu, Weiwei Li, Qian Li, Zhan Huang, Guibin Qiao, Yi-Long Wu
Journal: Journal of Clinical Oncology (2023)

e16013 Background: Neoadjuvant immunotherapy plus chemotherapy may enhance the resectability rate in locally advanced Esophageal Squamous Cell Carcinoma (ESCC). Nevertheless, due to the complex nature of the tumor immune microenvironment, an unmet need remains for biomarkers to identify NPC patients used to identify patients who benefit most from this neoadjuvant treatment strategy. Methods: Two independent cohorts of ESCC patients were enrolled in the study., including retrospective cohort (N=66) and prospective cohort (N=37). A total of 103 NPC FFPE samples were subjected to RNA sequencing. Single sample GSEA (ssGSEA) were performed to explore the Tumor microenvironment (TME). Differential genes associated with survival were analyzed using logistic regression and Kaplan-Meier methods. To reveal the expression of biomarker and TME, immunohistochemistry and multiplex immunofluorescence were used. Results: We demonstrated that COL19A1 high expression facilitates anti-PD-1 therapy [ COL19A1 high, OR (95% CI): 0.31 (0.1−0.97), p = 0.044]. COL19A1 high patients could benefit more from neoadjuvant immunotherapy (p &lt; 0.01), high mortality (63.3%, p &lt; 0.01), and have a trend towards a better RFS (p = 0.13) and OS (p = 0.056). Further analyses confirmed increased B cells infiltration and COL19A1 high expression could be seen in the immune-activated subgroup, which resulted in favorable survival and response to neoadjuvant immunotherapy plus chemotherapy. Conclusions: This study revealed an ESCC subpopulation presenting high COL19A1 expression, which responded well to neoadjuvant immunotherapy plus chemotherapy and was associated with good prognosis. It provided a convincing basis for designing biomarker-guided individual treatment.
Homologous recombination-related (HRR) gene mutation profiling and the association with TMB in Chinese patients with urological cancer.
Authors: Bin Yu, Huan Yi, Yangyang Yu, Mingzhe Xiao, Chuang Qi
Journal: Journal of Clinical Oncology (2023)

e16561 Background: Homologous recombination deficiency (HRD) is associated with tumorigenesis and could predict the response of PARP inhibitor (PARPi) therapy and immunotherapy. Loss of function or deleterious mutations in homologous recombination-related (HRR) genes contribute to HRD phenotype. Methods: Tumor tissue samples from 484 Chinese patients with urological cancer were sequenced with 551 cancer-related genes. 957 patients with WES data from the TCGA datasets were included for analysis. Results: In the Chinese cohort, 35.88% (47/131) bladder cancer (BCa) patients, 15.47% (28/181) renal cell carcinoma (RCC) and 37.21% (64/172) prostate cancer (PCa) patients exhibited somatic HRR (sHRR) gene mutations. The most frequently mutated genes were BRCA2 (12% in BCa, 5% in RCC) and CDK12 (17% in PCa), respectively. The germline HRR (gHRR) gene mutations were identified in 62.6% (82/131) BCa, 55.33% (96/180) RCC and 60.62% (97/160) PCa patients. The most frequently mutated gene was BRCA2 (24% in BC, 18% in RCC, 26% in PCa). 7.6% (10/131) BCa patients, 1.7% (3/181) RCC patients and 2.9% (5/173) Pca patients carried both germline and somatic HRR gene mutations. In the TCGA cohort, 38.69% (159/411) BCa patients, 11.62% (43/370) RCC and 6.25% (11/176) PCa patients exhibited somatic HRR (sHRR) gene mutations. The most frequently mutated gene was ATM (14% in BCa, 4% in RCC, 5% in PCa). Interestingly, for the patients with PCa, the somatic mutant frequency of HRR genes in Chinese cohort was higher than that in TCGA cohort (37.21% vs 6.25%, p &lt; 0.001). The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (Chinese cohort: BCa 13.97 vs 4.96, p &lt; 0.001; RCC, 4.96 vs 2.84, p &lt; 0.001; PCa, 5.64 vs 2.84, p &lt; 0.001, TCGA cohort: BCa, 7.21 vs 3.63, p &lt; 0.001; RCC, 1.68 vs 1.42, p = 0.003; PCa, 1.03 vs 0.71, p &lt; 0.001). However, the median TMB was similar between the gHRR-Mut and the gHRR-WT patients (Chinese cohort, BCa 6.38 vs 7.09 p = 0.646; RCC, 3.55 vs 2.84, p = 0.229; PCa, 3.55 vs 2.84, p = 0.111). Conclusions: Our data reported the genetic landscape of HRR gene in Chinese urological cancer patients and suggested that patients with altered HRR genes may be rational candidates for precision oncology treatment and provide new opportunities to predict the tumor response to multiple treatments.
The changes of HER3 expression in head and neck cancer patients treated with induction chemotherapy.
Authors: Joori Kim, Jeong-Oh Kim, Youn Soo Lee, Jung-Young Shin, Min Young Kim, Mi-Ran Lee, Seoree Kim, Saori Fujita-Sato, Maki Kobayashi, Tomoya Kakegawa, Jin Hyoung Kang
Journal: Journal of Clinical Oncology (2023)

e18004 Background: Erb-b2 receptor tyrosine kinase 3 (HER3) is broadly expressed in various types of cancer and is associated with poor prognosis. Recent evidence supports HER3 plays a role in acquired resistance to chemotherapy. The change of HER3 expression by chemotherapy in head and neck squamous cell carcinoma (HNSCC) remains unclear. Methods: We evaluated 95 patients with locally advanced HNSCC who had received induction chemotherapy (ICT) between 2009 and 2019. Immunohistochemical staining for HER3 was performed using formalin-fixed paraffin-embedded surgical specimens and biopsy samples. H-score of membrane staining was evaluated. Results: Median age of patients was 64 years, and 85% were male. Primary locations included oropharynx (54.8%), hypopharynx (21.5%), oral cavity (17.2%), and salivary gland (6.5%). Mean H-score of HER3 in tumor tissues was 77.6 ± 7.9. H-score of HER3 in HPV-positive tumors was higher than HPV-negative tumors (p = 0.019), which was more pronounced in oropharynx and hypopharynx tumors. While, H-score of HER3 in adjacent normal tissues of these tumors did not significantly differ. Compared with the non-smokers, tumor tissues of current or ex-smokers demonstrated higher H-score of HER3 (p = 0.033), independent of tumor location. In contrast, in adjacent normal tissues, no significant differences of H-score of HER3 were observed depending on the smoking status. The H-score higher than 100 was defined as HER3-high group. Among oropharynx and hypopharynx tumors with positive correlation between H-score of HER3 and HPV status (n = 56), HER3-high group was significantly correlated with HPV positivity (p = 0.009) and good response to ICT (p = 0.035). Good clinical response was also strongly related to HPV-positivity (p = 0.001). In addition, there was a tendency for longer overall survival in HER3-high group than low HER3 expression group (93 vs. 70 months, p = 0.053). The paired tumor samples collected at pre- and post-ICT (n = 21) were analyzed. HER3 expressions in adjacent normal tissue were higher at post-ICT compared to pre-ICT (p = 0.003), and these results were more pronounced in the non-smoking group, but no differences were found according to HPV-status. Conclusions: Taken together, our results showed that H-score of HER3 was significantly higher in both HPV-positive and smoking group. Interestingly, high HER3 expression in oropharynx and hypopharynx tumors was associated with HPV positivity and good clinical response to ICT. Additional analysis of tumor immune microenvironment in tumor tissues are underway.
Gemcitabine, cisplatin, nab-paclitaxel: The effectiveness of this regimen for gall bladder cancer.
Authors: Deepali Chaugule, Prabhat Ghanshyam Bhargava, Vikas S. Ostwal, Sujay Srinivas, Rajshree Nivrutti Patil, Aayushi Ghadi, Divya Vadodaria, Pritesh Naresh Munot, Ritam Joarder, Arvind Vaidyanathan, Mahesh Goel, Shraddha Patkar, Anant Ramaswamy
Journal: Journal of Clinical Oncology (2023)

e16168 Background: Locally Advanced inoperable/metastatic Gallbladder Cancers (GBC) are treated with either GC, GO, or single-agent Gemcitabine based on physician discretion. However, based on about 50% response rates (ORR) and prolonged survival in the phase II trial of biliary tract patients, were treated with Gemcitabine - Cisplatin - Nab-Paclitaxel (GCNP). Methods: Consecutive series of patients diagnosed with locally advanced (liver infiltration &gt; 5 cm, large nodes at porta, abutting duodenum), inoperable and metastatic biliary tract patients between January 2018 to August 2022 were evaluated for first-line chemotherapy GCNP, in the Multidisciplinary Joint Clinic (MDJC). The primary endpoint was ORR and the secondary endpoints were survival and tolerance. Results: A total of 142 patients received GCNP during the specified time period. The median age of the cohort was 52 years (range: 21- 79), the majority were females (61.3%), and the majority were GB (81.7%). Response rates were available in 137 patients. CR, PR, and SD were seen in 9 (6.3%), 87 (61.3%), and 24 (16.9%) respectively, for a RR of 67.6% and CBR of 84.5%. Median EFS was 9.92 (95% CI, 7.69- 12.14) months. Of the 52 patients in whom GCNP was given with NACT intent for locally advanced GBC, 17 patients underwent surgery (34%). Conclusions: Our study indicates that GCNP leads to better response rates, better chances of unresectable disease being surgically feasible at a later date, and possibly offers better survival in the GBC cohort.
Do we need to redefine the phoenix criteria after the arrival of the new generation imaging techniques?
Authors: Rodrigo Muelas, Clara Puerto Francés, Virginia Morillo, Angel L. Sanchez, Teresa Piquer, Encarnación Fernández Camacho, Vanessa Aznar-Tortonda, Patricia Plaza, Maria Mingarro de leon, Carlos Ferrer-Albiach
Journal: Journal of Clinical Oncology (2023)

e17018 Background: The biochemical recurrence (BCR) criteria are different depending on the primary tumour treatment: PSA ≥0.2 ng/mL after radical prostatectomy (RP) and PSA ≥ 2 ng/mL above the nadir after radiotherapy (RT)[Phoenix criteria]. The latter was established based on the detection of metastasis by conventional imaging tests (CT and bone scanning). Next generation imaging (NGI) techniques ( 18 F-choline PET/CT and specially 18 F-PSMA PET/CT), allow detection of metastasis with PSA values much lower than the Phoenix criteria. The purpose of this study is to compare the profile of patients diagnosed with metastatic hormone sensitive prostate cancer (mHSPC) by NGI techniques after BCR according to the primary tumour treatment performed. Methods: Patients diagnosed with mHSPC in our Radiation Oncology Department after BCR between February 2021 and December 2022 were reviewed. All of them underwent NGI: 18 F-choline PET/CT if there was BCR following RT or a PSA level &gt; 2 ng/ml after PTR; 18 F-PSMA PET/CT if there was BCR after PTR or if 18 F-choline PET/CT offered diagnostic uncertainties. Then, were stratified according to primary treatment: PTR (+/- salvage RT to the prostatic bed) vs RT (external or brachytherapy). PSA levels prior to NGI, number of metastases (≤5: oligometastatic vs &gt; 5: polymetastatic) and their location (M1a: exclusive lymph node metastasis, M1b: presence of bone metastasis and M1c: presence of visceral metastasis) were compared. Results: A total of 38 patients were idiagnosed with mHSPC: 42.1% after PTR and 57.9% after RT. PTR group had PSA levels prior to NGI of 1.08 ng/ml, of which 75% were 18 F-PSMA PET/CT. Twenty-five per cent of patients in this group were classified as polymetastatic. In RT group the median PSA levels prior to NGI was 3.5 ng/ml, of which 68.2% were 18 F-choline PET/CT. The proportion of polymetastatic patients was 50%. The location of metastases in PTR and RT group was: M1a (68.8% vs 59.1%), M1b (31.3% vs 36.4%) and M1c (0% vs 4.5%). Conclusions: The percentage of polymetastatic patients in RT group is double that of PTR group, which is a worse prognostic factor. (4). This difference in the number of metastases is due to the higher PSA levels prior to NGI in RT group, which is directly related to the definition established by the Phoenix criteria(3). Given that NGI techniques can detect metastases with PSA values below the Phoenix criteria, it would be reasonable to redefine it in order to reduce the percentage of polymetastatic patients through earlier detection and thus improve their prognosis.